Administration Of Androgen Deprivation Therapy Research Articles

Intermittent Versus Continuous Androgen Deprivation Therapy for Biochemical Progression After Primary Therapy in Hormone-Sensitive Nonmetastatic Prostate Cancer: Comparative Analysis in Terms of CRPC-M0 Progression

IntroductionTo analyze whether the use of an intermittent (IAD) versus continuous (CAD) androgen deprivation therapy for the treatment of biochemical progression after primary treatments in prostate cancer can influence the development of nonmetastatic castration resistant prostate cancer (CRPC-M0). Patients170 male patients with an histologically confirmed diagnosis of PC, presenting a biochemical progression after primary treatments (82 after radical prostatectomy and 88 after external radiation therapy), nonmetastatic at imaging were considered for continuous (85 cases) or intermittent (85 cases) administration of androgen deprivation therapy. Methodswe retrospectively collect all data regarding histological diagnosis, primary treatment, imaging for M0-M1 staging, PSA at progression, time to biochemical progression from primary therapy, ADT used, IAD cycles, so to compare in 2 groups (IAD vs. CAD) time for progression from the beginning of ADT treatment and type of progression in terms of CRPC-M0 versus CRPC-M1 cases. Resultsno significant (P= .4955) difference in the whole CRPC progression was found between IAD (25.8%) and CAD (30.5%) treatment at a mean of 32.7 ± 7.02 months and 35.6 ± 13.1 months respectively (P= .0738). Mean PSA at CRPC development was significantly higher in the IAD group (5.16 ± 0.68 ng/mL) than in the CAD group (3.1 ± 0.7 ng/mL) (P < .001). In all cases, imaging to detect M status at CRPC development was PET TC scan. At univariate analysis CAD administration significantly increases the RR for CRPC-M0 progression (RR 3.48; 95%CI 1.66-7.29; P = .01) when compared to the IAD administration, and this effect at multivariate analysis remained significant and independent to the other variables (RR 2.34, 95%CI 1.52-5.33; P = .03). Conclusionsin our population with biochemical progression after primary treatment for PC, the intermittent administration of ADT significantly reduces the risk to develop CRPC-M0 disease when compared to a continuous administration of ADT, whereas no difference between the 2 strategies in terms of CRPC-M1 progression exists.

Associations Between Intraductal Prostate Cancer and Metastases Following Radical Prostatectomy in Men With Prostate Cancer in the Veterans Affairs Database.

Intraductal carcinoma of the prostate (IDC-P) is a relatively unstudied feature present in some prostate cancer (PC) diagnoses with several studies suggesting associations with higher Gleason scores (GS) and earlier time to biochemical recurrence (BCR) after definitive treatment. We looked to identify cases of IDC-P in the Veterans Health Administration (VHA) database and measure associations between IDC-P and pathological stage, BCR, and metastases. Patients in the VHA database diagnosed with PC from 2000 to 2017, treated with radical prostatectomy (RP) at the VHA were included in the cohort. BCR was defined as post-RP PSA >0.2 or administration of androgen deprivation therapy (ADT). Time to event was defined as time from RP to event or censor. Differences in cumulative incidences were assessed through Gray's test. Associations with IDC-P and pathologic features at RP, BCR and metastases were assessed through multivariable logistic and Cox regression models. Of 13,913 patients meeting inclusion criteria, 45 patients had IDC-P. Median follow up was 8.8 years from RP. Multivariable logistic regressions showed patients with IDC-P were more likely to have GS ≥8 (Odds Ratio (OR) 1.14, P=.009) and higher T stages (T3 or 4 vs. T1 or 2 OR 1.14, P < .001). In total, 4,318 patients experienced a BCR, and 1,252 patients developed metastases of whom 26 and 12, respectively, had IDC-P. On multivariable regression IDC-P was associated with higher risk of BCR (IDC-P Hazard Ratio (HR) 1.71, P=.006) and metastases (HR 2.84, P < .001). Cumulative incidence of metastases at 4 years for IDC-P and non-IDC-P were 15.9% and 5.5% (P < .001) respectively. In this analysis, IDC-P was associated with higher Gleason score at RP, shorter time to BCR, and higher rates of metastases. Further studies are warranted to investigate the molecular underpinnings of IDC-P to better guide treatment strategies for this aggressive disease entity.

Replicating the timing of androgen deprivation therapy randomized trial (TROG 03.06 and VCOG PR 01-03 [TOAD]) for recurrent prostate cancer using real-world observational data.

e17090 Background: The landmark TOAD trial (Lancet Oncol 2016) demonstrated an overall survival benefit for immediate compared to delayed androgen deprivation therapy (ADT) for patients with recurrent prostate cancer or unsuitable for curative treatment. However, the extent to which TOAD trial results can be replicated in real-world population-based observational data is unknown. For these reasons, we used TOAD trial data and criteria to define a similar retrospective cohort of men with rising PSA after definitive treatment of localized prostate cancer to compare immediate versus delayed ADT for recurrent non-metastatic disease. Methods: We used two data sources to conduct this study: 1) TOAD trial data, and 2) national electronic health record, cancer registry, administrative, pharmacy, and laboratory data for men treated with radical prostatectomy or radiotherapy for localized prostate cancer and laboratory confirmed biochemical recurrence (BCR) between 2005- 2015 in the Veterans Health Administration. We defined BCR according to guidelines and used National Death Index data through 2019 for survival outcomes. We designated randomization to the ‘immediate’ and ‘delayed’ arms for men receiving ADT within (immediate) or after (delayed) 2 years of BCR in the observational data. We used Cox proportional hazards regression models adjusting for age, PSA at BCR, comorbidities, and Gleason score, stratified by prior ADT exposure, to compare survival outcomes for immediate versus delayed ADT. Results: We identified 9,866 men with BCR after radical prostatectomy, 3,431 after radiotherapy alone, and 2,703 after radiotherapy and adjuvant ADT. The mean age at randomization for the TOAD cohort was older (74.8 vs. 75.9 years, delayed vs. immediate) compared to our observational cohort (68.1 vs. 67.0 years, delayed vs. immediate). In unadjusted survival analyses, we found both overall and prostate cancer-specific survival were higher among patients with delayed ADT (log-rank p-value &lt; 0.001 for both). Our multivariable survival models among men with and without prior ADT exposure also demonstrated survival benefit associated with delayed ADT (prior ADT exposure, adjusted hazard ratio (aHR) 2.3, 95% confidence interval (CI) 1.7, 3.0, no prior ADT exposure 2.6, 95% CI 2.4, 2.8). Conclusions: The benefit of immediate ADT administration compared to delayed as reported within the TOAD study was not found in a comparable observational cohort of men with non-metastatic recurrent prostate cancer. Even after multivariable adjustment, we found clear association of delayed ADT administration with improved survival outcomes suggesting selection bias and unobserved confounding, or that delayed ADT may be warranted for selected patient populations necessitating further investigation. Source of Funding: NCI R01 CA242559.

PD15-01 SURVIVAL IN ADJUVANT VS SALVAGE RADIATION THERAPY IN PATHOLOGICAL NODE POSITIVE PROSTATE CANCER PATIENTS: A MULTICENTRIC STUDY

PD15-01 SURVIVAL IN ADJUVANT VS SALVAGE RADIATION THERAPY IN PATHOLOGICAL NODE POSITIVE PROSTATE CANCER PATIENTS: A MULTICENTRIC STUDY

MP80-18 SURVIVAL AFTER RADICAL PROSTATECTOMY VS RADIATION THERAPY IN CLINICAL NODE POSITIVE PROSTATE CANCER PATIENTS: A MULTICENTRIC STUDY

MP80-18 SURVIVAL AFTER RADICAL PROSTATECTOMY VS RADIATION THERAPY IN CLINICAL NODE POSITIVE PROSTATE CANCER PATIENTS: A MULTICENTRIC STUDY

Significant financial differences of chemical and surgical androgen deprivation in a contemporary cohort.

BackgroundAndrogen deprivation therapy (ADT) remains a cornerstone of treatment for advanced prostate cancer. Few men elect for surgical castration via bilateral orchiectomy. We sought to compare the relative difference in financial charges between chemical and surgical ADT in men.MethodsBilling data was obtained for patients with metastatic prostate cancer receiving chemical ADT and who had bilateral orchiectomy from 2014–2019. Men had chosen intervention based on personal preference. We compared charges of ADT administration for chemical ADT and overall charges for bilateral orchiectomy. We determined the time chemical ADT patient charges surpassed those of surgical charges, as well as the net present value (NPV) of hypothetical savings for electing surgery over various ADT agents.ResultsOne hundred and thirty-seven patients receiving chemical ADT and 7 patients who had undergone bilateral orchiectomy were analyzed. Median and mean surgical charges were $13,000. By 38 weeks following treatment initiation, 50% of chemical ADT patients had surpassed surgical charges, with 95% at 2 years. The NPV in savings for a median patient varied between ADT agent and was highest at $167,000 for leuprolide.ConclusionsIn less than a year, the median chemical ADT patient charges were greater than surgical castration. The NPV of electing surgery over ADT was the highest with leuprolide. Despite under-utilization, surgical castration remains a medically appropriate and cost-effective option for permanent ADT.

Stereotactic prostate radiotherapy with or without androgen deprivation therapy, study protocol for a phase III, multi-institutional randomized-controlled trial

Objective: The therapeutic landscape for localized prostate cancer (PC) is evolving. Stereotactic radiotherapy (SRT) has been reported to be at least not inferior to standard radiotherapy, but the effect of androgen deprivation therapy (ADT) in this setting is still unknown and its use is left to clinical judgment. There is therefore the need to clarify the role of ADT in association with SRT, which is the aim of the present study. Methods: We present a study protocol for a randomized, multi-institutional, Phase III clinical trial, designed to study SRT in unfavorable intermediate and a subclass of high-risk localized PC. Patients (pts) will be randomized 1:1 to SRT + ADT or SRT alone. SRT will consists in 36.25 Gy in 5 fractions, ADT will be a single administration of Triptorelin 22.5 mg concurrent to SRT. Primary end point will be biochemical disease-free survival. Secondary end points will be disease-free survival, freedom from local recurrence, freedom from regional recurrence, freedom from distant metastasis and overall survival (OS); quality of life QoL and patient reported outcomes will be an exploratory end point and will be scored with EPIC-26, EORTC PR 25, IPSS, IIEF questionnaires in SRT + ADT and SRT alone arms. Moreover, clinician reported acute and late toxicity, assessed with CTCAE v. 5.0 scales will be safety end points. Results: Sample size is estimated of 310 pts. For acute toxicity and quality of life results are awaited after 6 months since last patient in, whereas, for efficacy end points and late toxicity mature results will be available 3–5 years after last patient in. Conclusion: Evidence is insufficient to guide decision making concerning ADT administration in the new scenario of prostate ultra-hypofractionation. Hence, the need to investigate the ADT role in SRT specific setting. Advances in knowledge: The stereotactic prostate radiotherapy with or without ADT trial (SPA Trial) has been designed to establish a new standard of care for SRT in localized unfavorable intermediate and a subclass of localized high risk PC.

Luteinizing hormone-releasing hormone agonists for prostate cancer patients: routine clinical practice of Russian cancer urologists

Background. Despite the recent amendments to the guidelines for the treatment of metastatic hormone-sensitive prostate cancer (PCa) implying standard use of luteinizing hormone-releasing hormone (LHRH) agonists in combination with chemotherapy or androgen inhibitors, androgen deprivation therapy (ADT) remains an essential component of treatment for advanced PCa. Testosterone target castration level of 20 ng/dL implies routine measurement of testosterone levels along with prostate-specific antigen (PSA) levels during ADT. It is particularly interesting to evaluate the frequency of achieving castration testosterone level in routine clinical practice. Objective: to assess the frequency of achieving castration testosterone level (20 ng/dL) and maintaining it after 6 months of therapy in patients with hormone-sensitive PCa receiving an LHRH agonist for the first time. Materials and methods. In 2019-2020, Russian Society of Cancer Urologists conducted a non-interventional prospective multicenter study (observational program) aimed to evaluate the efficacy of LHRH agonist (including buserelin, goserelin, leuprorelin or triptorelin) in routine clinical practice in Russia. This study involved 39 cancer urologists and 479 patients aged 18 years and older diagnosed with hormone-sensitive PCa, who started their ADT with LHRH agonists for the first time regardless of the disease stage and previous treatment. Patients received hormone therapy with an LHRH agonist for at least 6 months, visiting their doctor every 3 months (visit 1; visit 2: after 3 months; visit 3: after 6 months). Results. Patients received one of the following drugs: leuprorelin (3.75 mg; 7.5 mg; 22.5 mg; 45 mg; n = 225; 47,0 %), goserelin (3.6 mg; 10.8 mg; n = 132; 27.5 %), buserelin (3.75 mg; n = 67; 14.0 %), and triptorelin (3.75 mg; 11.25 mg; n = 55; 11.5 %). Of 479 patients, 186 (38.8 %) received combination treatment with bicalutamide, 12 (2.5 %) with fluta-mide, 54 (11.3 %) with zoledronic acid, and 11 (2.3 %) with denosumab. Among 146 patients with metastatic PCa, a combination of ADT plus docetaxel was administered to 30 participants (20.6 %), ADT plus abiraterone to 8 participants (5.5 %), and ADT plus enzalutamide to 2 participants (1.4 %). After 6 months of therapy, mean PSA level decreased by 94.2 % (from baseline 118.12 ng/mL to 6.87 ng/mL). Mean testosterone level was 19.0 ng/dL (range: 0.029-100 ng/dL). Among 430 patients, the targeted testosterone level &lt;20 ng/dL was achieved in 257 individuals (59.8 %); the level of 20-50 ng/dL was achieved in 158 individuals (36.7 %); and fifteen patients (3.5 %) had their testosterone level &gt;50 ng/dL. The incidence of adverse events was low; most of them were mild. Conclusion. Our findings suggest that not all patients achieve targeted testosterone level of &lt;20 ng/dL, which corroborates the need for routine monitoring of testosterone levels during therapy to ensure its timely correction. We observed frequent administration of ADT with maximum androgen blockade. In patients with metastatic PCa, the use of standards for combination treatment with docetaxel and androgen inhibitors is limited.

Definition and Impact on Oncologic Outcomes of Persistently Elevated Prostate-specific Antigen After Salvage Lymph Node Dissection for Node-only Recurrent Prostate Cancer After Radical Prostatectomy: Clinical Implications for Multimodal Therapy

BackgroundThe optimal definition and prognostic significance of persistently elevated prostate-specific antigen (PSA) after salvage lymph node dissection (sLND) for node-only recurrent prostate cancer (PCa) remain unknown. ObjectiveTo assess the definition and clinical implications of persistently elevated PSA after sLND for node-only recurrent PCa after radical prostatectomy. Design, setting, and participantsThe study included 579 patients treated with sLND at 11 high-volume centers between 2000 and 2016. Outcome measurements and statistical analysisWe assessed the linear relationship between the first PSA after sLND and death from PCa. Different definitions of PSA persistence were included in a multivariable model predicting cancer-specific mortality (CSM) after surgery to identify the best cutoff value. We investigated the association between PSA persistence and oncologic outcomes using multivariable regression models. Moreover, the effect of early androgen deprivation therapy (ADT) after sLND was tested according to PSA persistence status and estimated risk of CSM. Results and limitationsWe found an inverse relationship between the first PSA after sLND and the probability of cancer-specific survival. PSA persistence defined as first postoperative PSA ≥0.3 ng/ml provided the best discrimination accuracy (C index 0.757). According to this cutoff, 331 patients (57%) experienced PSA persistence. The median follow-up for survivors was 48 mo (interquartile range 27–74). After adjusting for confounders, men with persistently elevated PSA had higher risk of clinical recurrence (hazard ratio [HR] 1.61), overall mortality (HR 2.20), and CSM (HR 2.59; all p < 0.001) after sLND. Early ADT administration after sLND improved survival only for patients with PSA persistence after surgery (HR 0.49; p = 0.024). Similarly, when PSA persistence status was included in multivariable models accounting for pathologic features, early ADT use after sLND was beneficial only for patients with a predicted risk of CSM at 5 yr of >10%. ConclusionsPSA persistence after sLND independently predicts adverse prognosis, with the best discrimination accuracy for CSM provided by a definition of PSA ≥ 0.3 ng/ml. We showed that when stratifying patients by final pathology results and PSA persistence status, early ADT use after sLND was beneficial only for patients with PSA persistence or with a calculated 5-yr risk of CSM of >10%, which could be useful as we await results from ongoing prospective trials. Patient summaryWe found that for patients with prostate cancer who had lymph nodes removed after their cancer recurred, persistently elevated prostate-specific antigen (PSA) levels predict poorer prognosis. We showed that a PSA level of ≥0.3 ng/ml provides the best accuracy in identifying patients with worse prognosis. This may help to improve risk stratification after lymph node removal and allow physicians to optimize treatment strategies after surgery.

Abstract PO-046: Single-cell profiling of tumor evolution and complex immune infiltrate induced by ADT and PD-1 blockade in metastatic hormone-sensitive prostate cancer

Abstract Patients presenting with de novo metastatic, hormone-sensitive prostate cancer (mHSPC), while initially responsive to androgen deprivation therapy (ADT), invariably progress to castration-resistant prostate cancer. We and others have shown that ADT induces a complex immune infiltrate in localized prostate cancer, in both animal models and humans, leading to trials of combination ADT with immunotherapy, but the effect of ADT alone or in combination with checkpoint blockade have not been well-described in metastatic tumor sites. We are conducting a clinical trial (NCT03951831) to test the hypothesis that ADT-induced immune infiltrate can be further augmented with anti-PD-1 inhibition in men with mHSPC. Here, we present single-cell RNA-sequencing analysis of paired metastatic tumor biopsies at baseline and on-treatment. In our phase 2, open-label, single-center trial, eligible patients with mHSPC are treated with phased administration of ADT, cemiplimab (anti-PD-1 inhibitor), and docetaxel. All patients undergo baseline metastatic tumor biopsies as well as on-treatment biopsies after either ADT alone or ADT in combination with cemiplimab. Biopsies are collected from bone, lymph node, and liver metastases, and are dissociated by gentleMACS protocol for sequencing using the 10X Chromium platform. Cells are first clustered at the transcriptional level by unsupervised Louvain algorithm with optimization of the resolution parameter by a novel silhouette-score subsampling technique. Cells are further sub-clustered following inference of protein activity by the VIPER algorithm. Cell types are assigned by singleR and tumor cells verified by inference of Copy Number Variations (InferCNV). Baselines are compared to their paired on-treatment sample. Differences in treatment-induced immune cell fold-change are compared for patients profiled following ADT only (n=3) and patients profiled following ADT in combination with checkpoint blockade (n=2). Furthermore, transcriptional and proteomic profiles of tumor cells persisting after treatment are compared to those present before treatment to identify consistent treatment-induced changes in tumor cell state. Preliminary results showed significant increase in the fold-change of CD8+ T cells in combination-treated samples relative to baseline (P &amp;lt; 0.001), which was not observed in patients treated with ADT only. There was also a dramatic shift in other immune cell types with treatment, including macrophages and Treg. In addition, we found a consistent up-regulation of antigen-presentation in tumor cells following ADT, and identified that tumor cells expressing KLK2/KLK3 significantly dissipate with treatment (mean fold-change 0.56, P &amp;lt; 0.001). Taken together, these data demonstrate the feasibility of scRNA-seq on prostate cancer metastatic lesions and provide initial support for the hypothesis that ADT in combination with checkpoint blockade induces complex immunological changes in the metastatic tumor microenvironment. Citation Format: Aleksandar Obradovic, Jessica Hawley, Xinzheng Guo, Matthew Chaimowitz, Matthew Dallos, Mark Stein, Andrea Califano, Charles Drake. Single-cell profiling of tumor evolution and complex immune infiltrate induced by ADT and PD-1 blockade in metastatic hormone-sensitive prostate cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Tumor Heterogeneity: From Single Cells to Clinical Impact; 2020 Sep 17-18. Philadelphia (PA): AACR; Cancer Res 2020;80(21 Suppl):Abstract nr PO-046.

Quantifying observational evidence for risk of dementia following androgen deprivation therapy for prostate cancer: an updated systematic review and meta-analysis.

Androgen deprivation therapy (ADT) administration was recently reported and might be positively associated with dementia. However, the existing studies showed controversial results. The aim of this study was to evaluate the relationship between ADT and the risk of dementia through a meta-analysis. Original articles published up to March 2020 were retrieved from Embase, Pubmed, the Cochrane library, and Web of Science for studies focusing on associations between ADT for prostate cancer (PCa) and incidence of dementia. A meta-analysis was conducted using a hazard ratio (HR) and 95% confidence interval (CI) as effect measures. Heterogeneity between the studies was examined using I2 statistics. Subgroup analyses, sensitivity analyses, and meta-regression were conducted, and publication bias was assessed by Egger's test. Thirteen studies were included in this systematic review. Eleven cohort studies involving 339,400 cases and 436,851 controls were included in the main meta-analysis. ADT administration was associated with a 21% increase in dementia risk (pooled HR = 1.21, 95% CI: 1.13-1.30, P < 0.001). Subgroup analyses based on ADT types showed that luteinizing hormone-releasing hormone agonists (HR = 1.14, P < 0.001), bilateral orchiectomy (HR = 1.42, P < 0.001), oral antiandrogens (HR = 1.35, P = 0.138), and combined androgen blockade (HR = 1.22, P = 0.097) were positively related to subsequent risk of dementia, although the differences were not statistically significant with oral antiandrogens and combined androgen blockade. The current study indicated that ADT administration, no matter with types of ADT, is associated with the risk of dementia in patients with PCa. Future studies are needed to determine whether ADT causes dementia or is merely associated with increased risk.

Metastasis-directed Therapy (SBRT) Guided by PET-CT 18F-CHOLINE Versus PET-CT 68Ga-PSMA in Castration-sensitive Oligorecurrent Prostate Cancer: A Comparative Analysis of Effectiveness.

The present analysis aims to compare the impact of 18F-fluorocholine (18F-choline) and gallium-68 prostate-specific membrane antigen (68Ga-PSMA) positron emission tomography (PET)-computed tomography (CT)-guided metastases-directed therapies (MDTs) in patients with castration-sensitive oligorecurrent prostate cancer (PC). Inclusion criteria were: (1) histologically proven prostate adenocarcinoma; (2) evidence of biochemical relapse after primary tumor treatment; (3)≤ 3 hypermetabolic oligorecurrent lesions detected by 18F-choline or 68Ga-PSMA PET-CT; (4) PET-CT imaging performed in a single nuclear medicine department; (5) patients treated with upfront stereotactic body radiotherapy (SBRT) without hormone therapy; and (6) SBRT delivered with a dose per fraction≥ 5 Gy. In the case of oligoprogression (≤ 3 lesions outside the previous RT field) after MTD, a further course of SBRT was proposed; otherwise, androgen deprivation therapy (ADT) was administered. A total of 118 lesions in 88 patients were analyzed. Forty-four (50%) patients underwent 68Ga-PSMA PET-guided SBRT, and the remaining underwent choline PET-based SBRT. The median follow-up was 25 months (range, 5-87 months) for the entire cohort. Overall survival and local control were both 100%. Distant progression occurred in 48 (54.5%) patients, for a median distant progression-free survival of 22.8 months (range, 14.4-28.8 months). The median pre-SBRT prostate-specific antigen was 2.04 ng/mL in the choline PET cohort and 0.58 ng/mL in the PSMA-PET arm. Disease-free survival rates were 63.6% and 34%, respectively, in the 68Ga-PSMA and choline PET group (P= .06). The ADT administration rate was higher after choline-PET-guided SBRT (P= .00) owing to the higher incidence of polymetastatic disease after first-course SBRT compared with 68Ga-PSMA-based SBRT. In the setting of oligorecurrent castration-sensitive PC, PSMA-PET-guided SBRT produced a higher rate of ADT-free patients when compared with the 18F-choline-PET cohort. Randomized trials are advocated.

Long-term Outcomes of Salvage Lymph Node Dissection for Nodal Recurrence of Prostate Cancer After Radical Prostatectomy: Not as Good as Previously Thought

BackgroundLong-term outcomes of patients treated with salvage lymph node dissection (sLND) for nodal recurrence of prostate cancer (PCa) remain unknown. ObjectiveTo investigate long-term oncological outcomes after sLND in a large multi-institutional series. Design, setting, and participantsThe study included 189 patients who experienced prostate-specific antigen (PSA) rise and nodal-only recurrence after radical prostatectomy (RP) and underwent sLND at 11 tertiary referral centers between 2002 and 2011. Lymph node recurrence was documented by positron emission tomography/computed tomography (PET/CT) scan using either 11C-choline or 68Ga prostate-specific membrane antigen ligand. Outcome measurements and statistical analysisThe primary outcome of the study was cancer-specific mortality (CSM). The secondary outcomes were overall mortality, clinical recurrence (CR), biochemical recurrence (BCR), and androgen deprivation therapy (ADT)-free survival after sLND. The probability of freedom from each outcome was calculated using Kaplan-Meier analyses. Cox regression analysis was used to predict the risk of prostate CSM after accounting for several parameters, including the use of additional treatments after sLND. Results and limitationsAt long term, 110 and 163 patients experienced CR and BCR, respectively, with CR-free and BCR-free survival at 10 yr of 31% and 11%, respectively. After sLND, a total of 145 patients received ADT, with a median time to ADT of 41 mo. At a median (interquartile range) follow-up for survivors of 87 (51, 104) mo, 48 patients died. Of them, 45 died from PCa. The probabilities of freedom from cancer-specific and all-cause death at 10 yr were 66% and 64%, respectively. Similar results were obtained in sensitivity analyses in patients with pelvic-only positive PET/CT scan, as well as after excluding men on ADT at PET/CT scan and patients with PSA level at sLND higher than the 75th percentile. At multivariable analyses, patients who had PSA response after sLND (hazard ratio [HR]: 0.45; p = 0.001), and those receiving ADT within 6 mo from sLND (HR: 0.51; p = 0.010) had lower risk of death from PCa. ConclusionsA third of men treated with sLND for PET-detected nodal recurrence of PCa died at long term, with PCa being the main cause of death. Salvage LND alone was associated with durable long-term outcomes in a minority of men who significantly benefited from additional treatments after surgery. Taken together, all these data argue against the use of metastasis-directed therapy alone for patients with node-only recurrent PCa. These men should instead be considered at high risk of systemic dissemination already at the time of sLND. Patient summaryWe assessed long-term outcomes of patients treated with salvage lymph node dissection (sLND) for node-recurrent prostate cancer (PCa). In contrast with prior evidence, we found that the majority of these men recurred after sLND and eventually died from PCa. A significant survival benefit associated with the administration of androgen deprivation therapy after sLND suggests that sLND should be considered part of a multimodal approach rather than an exclusive treatment strategy.

Efficacy of Leuprorelide acetate (Eligard®) in daily practice in Brazil: a retrospective study with depot formulations in patients with prostate cancer

ABSTRACTIntroduction:Androgen deprivation therapy (ADT) is the mainstay of therapy for advanced prostate cancer. Studies addressing the efficacy of different depot formulations of long acting luteinizing hormone releasing hormone agonists in the Brazilian population are lacking. We aimed to compare the efficacy of three schedules of leuprolide acetate in lowering PSA in a real world population.Materials and Methods:We reviewed the medical records of patients with prostate cancer seen at our institution between January 2007 and July 2018. We analyzed patients treated with long-acting leuprolide acetate and grouped these patients into three strata according to the administration of ADT every 1, 3 or 6 months. The primary outcome was the serum prostate specific antigen (PSA) levels at 6 and 12 months after treatment initiation. We used Friedman test to compare the distribution of PSA levels at baseline and at 6 and 12 months within each treatment stratum. We considered two-sided P values <0.05 as statistically significant. We analyzed toxicity descriptively.Results:We analyzed a total of 932 patients, with a median age of 72 years and a median time since diagnosis of prostate cancer of 8.5 months. ADT was administered monthly in 115 patients, quarterly in 637, and semiannually in 180. Nearly half of the patients had locally advanced disease. In comparison with baseline, median serum PSA levels were reduced at 12 months by at least 99.7% in the three strata (P <0.001 in all cases). Sexual impotence and hot flashes were the most frequently reported toxicities.Conclusion:To our knowledge, this is the largest assessment of real-world data on alternative schedules of leuprolide in a Brazilian population. Our study suggests that PSA levels can be effectively be reduced in most patients treated with monthly, quarterly, or semiannual injections of long-acting leuprolide acetate.

Use and outcomes in men with metastatic castration-sensitive prostate cancer (mCSPC) treated with docetaxel in addition to androgen deprivation therapy (ADT): Analysis of real-world data in the United States (US).

e19322 Background: mCSPC patients treated with docetaxel + androgen deprivation therapy (D+ADT) demonstrate increased overall survival (OS)1,2. However, limited real-world outcome data is available for such patients. This study assesses the real-world use and outcomes with D+ADT in mCSPC in the US. Methods: Adult (≥18 years old) men with mCSPC (defined as men with metastasis at index diagnosis of prostate cancer [de novo] or those who progressed to mCSPC after prior diagnosis of localized disease) were retrospectively identified from the Optum (2007–2018) and SEER Medicare (2007–2016) databases. Men diagnosed with mCSPC in or after 2014 with exposure to docetaxel and no brain metastasis were included for analysis. Patients were characterized based on age; baseline prostate specific antigen (PSA) level; administration of ADT; prior radiotherapy (RT); prior radical prostatectomy (RP); presence of visceral disease, bone or bone + visceral metastases; and treatment duration of docetaxel. OS and time to metastatic castration-resistant prostate cancer (mCRPC) were measured. Results: Among 4959 men identified with mCSPC during or after 2014, 192 (3.8%) received D+ADT ± Bicalutamide as first line systemic therapy. Baseline characteristics are presented in the Table below. Mean ± SD duration of docetaxel exposure was 115 ± 84.2 days (median 118 days). Median OS among these men was 30.5 (28.1, 36.7) months and median time to mCRPC was 18.3 (14.5, 24.6) months. Only 9% of men received docetaxel for ≥6 cycles (180 days); median OS in these men was NR (19.1- NR) with 74% surviving at 2 years compared to 65% surviving at 2 years in those with docetaxel duration &lt;6 cycles. Conclusions: Use of docetaxel in the real-world mCSPC patient population in the US is limited. Majority of men received less than the recommended dose of 6 cycles. OS with D+ADT in real-world patients with mCSPC appears to be lower than the OS reported in published trials.

Evaluation of immune-related adverse events (irAE): Utilizing the patient-reported outcomes of the common terminology criteria for adverse events (PRO-CTCAE) in a phase II study of ipilimumab (ipi) in men with castration-sensitive prostate cancer (CSPC).

e24174 Background: Incorporation of the PRO-CTCAE during chemotherapy is associated with fewer ER visits and improved survival. Limited data exist using this tool to capture irAE in immunotherapy trials. We collected select PRO-CTCAEs in a clinical trial evaluating an immune checkpoint inhibitor (ICI) in patients (pts) with CSPC. Methods: Cohort A (Coh A) enrolled de novo metastatic CSPC; Cohort B (Coh B) enrolled recurrent CSPC after radical prostatectomy (RP). Treatment consisted of 4 doses of ipi and 8 months of androgen deprivation therapy (ADT) in Coh A &amp; B, and RP in Coh A. PRO-CTCAEs were collected at each ipi or ADT administration, and during follow-up. PRO-CTCAE items included abdominal pain, diarrhea, fatigue, anorexia, nausea, vomiting, rash and pruritus, with the correspondent attributes of frequency (freq), severity (sev), interference (int), and presence. Results: 16 pts were treated (Coh A: 7; Coh B: 9) with 181 matched pairs of PRO-CTCAE and CTCAE. The study was terminated early for an unfavorable risk:benefit ratio. PRO-CTCAE completion at required visits was 85.4% in Coh A and 98.1% in Coh B. Cohen’s kappa coefficients was lowest for pruritus (k = 0.10, slight agreement) and highest for rash (k = 0.64, moderate agreement). CTCAE captured diarrhea in 10 pts, 4 of whom received steroids. 75% (3/4) of pts receiving steroids graded diarrhea as ‘frequently’ or ‘almost constantly’ on the PRO-CTCAE while 66.7% (4/6) of those who did not receive steroids reported the same frequency. Conclusions: IrAE were more commonly reported and of higher grade by patients using the PRO-CTCAE as compared to clinician reporting, consistent with existing literature in non-ICI studies. Diarrhea as reported by the PRO-CTCAE did not associate with steroid use in this small trial. Further studies are needed to evaluate irAE using PRO-CTCAEs and the potential role in management of these toxicities. Clinical trial information: NCT02020070 . [Table: see text]

Dissecting the immune infiltrate induced by ADT and PD-1 blockade in men with metastatic hormone-sensitive prostate cancer using single-cell RNA-sequencing.

e17548 Background: Overall survival of men with de novo metastatic, hormone-sensitive prostate cancer (mHSPC) is improved by treatment intensification with docetaxel and hormone therapy compared to androgen deprivation therapy (ADT) alone. However, castration-resistant prostate cancer (CRPC) invariably develops. We and others have shown that ADT induces a robust and complex immune infiltrate in localized prostate cancer, in both animal models and humans. We are conducting a clinical trial (NCT03951831) to test the hypothesis that the ADT-induced immune infiltrate can be further augmented with chemotherapy and an anti-PD-1 inhibitor in men with mHSPC. Here, we present single-cell RNA-sequencing analysis of paired metastatic tumor biopsies at baseline and on-treatment. Methods: In our phase 2, open-label, single-center trial, eligible patients with mHSPC are treated with phased administration of ADT, cemiplimab (anti-PD-1 inhibitor), and docetaxel. All patients undergo baseline metastatic tumor biopsies as well as on-treatment biopsies after either ADT alone or ADT in combination with cemiplimab. Biopsies are dissociated by gentleMACS protocol, and single cells are sequenced using the 10X Chromium platform. Cells are Quality-control filtered to those with over 1000 Unique Molecular Identifiers and less than 25% mitochondrial RNA, then clustered on global gene expression and on inferred protein activity by unsupervised Louvain algorithm with silhouette score selection of optimal clustering resolution. Cell types are assigned by the singleR algorithm and tumor cell identity is verified by inference of Copy Number Variations (InferCNV). Differential gene expression across sub-clusters is performed, and baselines will be compared to their paired on-treatment sample (N = 3). Results: Preliminary results showed a significant increase in the normalized fold-change of CD8+ T cells in on-treatment samples relative to baseline samples (P &lt; 0.001). There was also a dramatic increase in other immune cell subtypes with treatment. In addition, we found a shift in transcriptional state of tumor cells and that tumor cells expressing KLK2/KLK3 significantly dissipate with treatment (normalized fold-change 0.56, P &lt; 0.001). Conclusions: Taken together these show the feasibility of SS-RNA-seq on PC metastatic lesions and provide initial support for the hypothesis that ADT induces complex immunological changes in the tumor microenvironment (TME) in metastatic prostate tumors.

Androgen deprivation therapy and the risk of iron-deficiency anaemia among patients with prostate cancer: a population-based cohort study.

ObjectivesThe administration of androgen deprivation therapy (ADT) to patients with metastatic prostate cancer might be associated with some adverse effects such as anaemia; however, few studies have been performed in East Asian populations. This study aimed to investigate the association between ADT and iron-deficiency anaemia (IDA) among patients with prostate cancer in a population-based nationwide cohort.DesignCohort study.SettingTaiwan.ParticipantsData for the cohort study were retrieved from the Taiwan National Health Insurance Research Database. Propensity score matching was used to select 7262 patients with prostate cancer who received ADT as the study group and 3631 patients who did not receive ADT as the control group.Primary and secondary outcome measuresThis study individually tracked patients over a 3-year study period and identified those who were subsequently diagnosed with IDA following the index date.ResultsThe incidence rates of IDA in the study and control groups were 1.66 (95% CI CI 1.45 to 1.86) and 1.01 per 100 person-years (95% CI 0.78 to 1.25), respectively. Furthermore, proportional Cox regression revealed an HR of 1.62 (95% CI 1.24 to 2.12) for IDA in the study group after adjusting for patients’ age, monthly income, geographic location, residential urbanisation level and incidence of hyperlipidaemia, diabetes, hypertension, coronary heart disease, inflammatory bowel disease, other cancers and gastrointestinal bleeding.ConclusionCompared with its non-use among patients with prostate cancer, ADT use was associated with a higher risk of IDA.

Predictive Factor to Castrate-Resistant Prostate Cancer (CRPC) after Primary Androgen Deprivation Therapy (ADT): Single Center Experience in Indonesia

ADT is the main therapy in prostate cancer, especially in advanced stages, although ADT does not limit the progression of this disease to become CRPC, where the mortality rate will be much higher when CRPC has occurred. This study aims to examine corellating factors influenced the short duration to CRPC after primary ADT administration. 205 prostate cancer patients with CRPC or mCRPC in Saiful Anwar Malang Hospital from 2013 to 2018 were included in this study. Data recorded were age, initial PSA level, Gleason score, prostate cancer stage, type of ADT, nadir PSA, time between ADT and nadir PSA, and testosterone levels after ADT. To see the independent factors that influence the occurrence of CRPC, the Cox proportional hazards regression model was used. The average age of patients was 67, 53  6.86 years with an average level of initial PSA of 674.87  1405.80 80 / dL. The average time for CRPC to occur was 24.7  9.74 months. In multivariate analysis it was found that the stage of cancer with metastasis (HR 1,616, p 0,048), testosterone level after ADT was &gt; 20ng / dL (HR 4,638, p 0,000), nadir PSA &gt; 4ng / dL (HR 1,716, p 0,023) and time to reach Nadir PSA &lt;6 months (HR 1.596, p 0.004) is a significant independent factor for CRPC occurrence. The conclusion is cancer stage, testosterone levels after ADT, nadir PSA and time needed to reach nadir PSA were independent factors for CRPC in patients with prostate cancer who had primary ADT.

Is androgen deprivation therapy for prostate cancer associated with cardiovascular disease? A meta-analysis and systematic review.

Androgen deprivation therapy (ADT) is widely being applied in men who suffered from prostate cancer. Whether androgen deprivation therapy (ADT) is associated with an increased risk of developing cardiovascular-related disease is poorly defined. The aim of the present meta-analysis is to explore the relationship between ADT and the risk of cardiac events. MATERIALS ANDMETHODS: For this systematic review andmeta-analysis, we searched databases from inception to April 2019 for randomized controlled trials (RCT) or observational studies that reported data on ADT administration and cardiac event incidence. The connection was evaluated through estimating relative risk ratio (RR) and 95% confidence intervals (CIs). A significantly increased acute myocardial infarction (AMI) was detected in the ADT group compared with the control group (RR=1.19, 95% confidence interval (CI), 1.02-1.39, P<.05). A significant difference between cardiovascular disease (CVD) and ADT was also observed, with summary RR=1.25, 95% CI, 1.11-1.40, P<.05. Furthermore, our study also suggested ADT was not related to increased incidence of sudden cardiac death (SCD) (RR=1.13, 95% CI, 0.92-1.38,P=.24); AMI and CVD were not connected with the duration of ADT (AMI: RR=1.31; 95% CI, 0.66-2.63, P=.44, for>5year group; CVD: RR=1.12, 95% CI, 0.97-1.30, P=.12, for >5year group). In addition, the RR for risk of CVD was 1.28 (95% CI, 1.01-1.62, P<.05) for men with PCa on new hormonal agents. Various ADT modalities have different impact on cardiovascular disease risk in different level. Long-term application of ADT is not associated with increased risk of AMI and CVD. Both abiraterone and enzalutamide could significantly increase the incidence of cardiac events in patients who suffered from prostate cancer. Cautions and periodic cardiovascular elevation are necessary for patients before the ADT starting. Androgen deprivation therapy is associated with increased risk of AMI, CHD, in contrast, this association is not detected in SCD.